Cell-to-cell spread of HIV keeps viral reservoir going despite ART

An infected cell, outlined by the green fluorescent HIV it contains, transmits HIV to uninfected target cells (in red). Photo: Benjamin K. Chen, Mount Sinai School of Medicine.
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The presence of very low levels of HIV in the blood despite treatment with highly potent antiretroviral regimens could be explained by cell-to-cell spread of the virus that overwhelms drug concentrations within cells, according to new research from the laboratory of US Nobel prize winner David Baltimore.

The study, published today in the journal Nature, is an attempt to explain why, despite reducing HIV replication to very low levels, highly potent regimens that target several different steps in the HIV life cycle cannot shut down HIV replication altogether.

The findings imply that the development of drug delivery methods that can raise drug concentrations within cells vulnerable to HIV infection could stop this process – and gradually shrink the reservoir of HIV-infected cells that maintain infection within the body. This would aid efforts to cure HIV infection, although it is unlikely to cure HIV infection alone.

Glossary

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

cure

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

reservoir

The ‘HIV reservoir’ is a group of cells that are infected with HIV but have not produced new HIV (latent stage of infection) for many months or years. Latent HIV reservoirs are established during the earliest stage of HIV infection. Although antiretroviral therapy can reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive (a phenomenon called residual inflammation). Latently infected cells may be reawakened to begin actively reproducing HIV virions if antiretroviral therapy is stopped. 

lymph nodes

Bean-sized structures throughout the body's lymphatic system, where immune cells congregate to fight infections. Clusters of lymph nodes are found in the underarms, the groin, and the neck.

latent reservoir

The ‘HIV reservoir’ is a group of cells that are infected with HIV but have not produced new HIV (latent stage of infection) for many months or years. Latent HIV reservoirs are established during the earliest stage of HIV infection. Although antiretroviral therapy can reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive (a phenomenon called residual inflammation). Latently infected cells may be reawakened to begin actively reproducing HIV virions if antiretroviral therapy is stopped. 

Researchers at the California Institute of Technology compared the effects of the drugs in one of the most potent antiretroviral combinations (tenofovir, emtricitabine and efavirenz) on suppressing HIV spread in cell cultures.

They found that cell-free infection – where cells become infected by virions that have been released from other cells – was efficiently prevented by tenofovir and efavirenz. In the presence of tenofovir cell-free infection declined thirty-fold.

However, infections that occurred by the transfer of virus through direct contact between cells were much less affected by the presence of drug. At the highest drug concentrations, the transmission rate due to cell-to-cell infection was six times higher than the rate of cell-free infection.

"We saw that with cell-to-cell infection, you wind up with a lot more virus infecting a single cell," explained Alex Sigal, a postdoctoral scholar in Baltimore's laboratory and lead author of the study. "When this happens, the chance of at least a single virus getting past the drugs is much larger."

In fact, they found that whereas cell-free infection might transmit one virus, in the presence of tenofovir or efavirenz respectively, an average of 75 and 175 viruses were being transferred from one cell to another when direct transfer took place.

"And you only need one virus to infect a cell and keep the cycle going, forming a reservoir of infection," said Sigal.

Furthermore, once infection became established as a result of cell-to-cell transfer, the number of infected cells in the test tube kept growing despite tenofovir concentrations similar to those achieved by normal dosing. It was only when tenofovir concentrations were at their peak that the number of infected cells began to decline slightly with each cycle of virus replication.

This finding implies that getting more drug into cells, and keeping it there, would limit replication as a result of cell-to-cell spread, but it’s unclear at this stage whether higher drug levels would stop it in the first place.

Determining the location of viral reservoirs in the body, as well as mechanisms that maintain it, are important parts of the search for an HIV cure. Eliminating the reservoir, or at least finding ways of keeping it from spurring new rounds of HIV replication, will be essential because, at the moment, the reservoir of infected cells is enough to cause a huge rebound in viral load within weeks of stopping antiretroviral treatment.

"It's important to determine whether or not cell-to-cell replication is causing a reservoir, particularly in terms of finding a cure," said Sigal. "You can't treat it the same way as you would a latent reservoir."

Strategies to `wake up` virus in resting cells so that it could be cleared by antiretroviral drugs would not address cell-to-cell spread of the virus.

"For us, the next step is to look at the process on a more physiological level by looking at how HIV infects in organs such as lymph nodes where cell-to-cell transmission actually happens," said Sigal.

"We're really looking for a cure, but to get to a cure, you have to fully understand the disease first," he said.

References

Sigal A et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature, advance online publication, August 17, 2011.